tbuckley/cabot-search huggingface dataset:
High atezolizumab antidrug antibody levels are associated with unfavorable clinical outcomes and diminished T cell responses following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.
Authors: Hong Jae Chon, Chan Kim, Hannah Yang, Ilhwan Kim, Beodeul Kang, Hyeyeong Kim, Hyunho Kim, Won Suk Lee, Sanghoon Jung, Ho Yeong Lim, Jaekyung Cheon
Journal: Journal of Clinical Oncology (2022)

4105 Background: Systemic administration of humanized monoclonal antibodies can be immunogenic and trigger unwanted anti-drug antibody (ADA) responses. In the IMbrave 150 study, 29.6% of advanced hepatocellular carcinoma (HCC) patients developed atezolizumab ADAs after atezolizumab and bevacizumab (atezo/bev) treatment. ADAs could impair the action of the therapeutic antibody by reduction of serum concentration or neutralization. We determined the clinical and immunological implications of high ADA levels in advanced HCC patients after atezo/bev treatment. Methods: Advanced HCC patients (n = 132) treated with first-line atezo/bev were prospectively enrolled (discovery cohort: 50 from an institute; validation cohort: 82 from four institutes). Serum levels of atezolizumab ADA at baseline and three weeks (C2D1) and atezolizumab concentrations at C2D1 were measured by competitive ELISA. The effects of ADA on T cell immunity were examined by multiplex flow cytometry. Results: Strong ADA (≥ 1000 ng/ml) responses at C2D1 were observed in 17.4% of advanced HCC patients. ADA elevation after atezo/bev at C2D1 was evident in non-responders but not significant in responders. In the discovery cohort, patients with high ADA at C2D1 showed a decreased response rate (ADA-high: 11% and ADA-low: 34%) and shorter progression-free survival (PFS) and overall survival (OS) with atezo/bev compared to those with low ADA levels ( P = 0.004 for PFS; P = 0.009 for OS). In the validation cohort, patients with high ADA at C2D1 showed reduced response rate than those with low ADA (ADA-high: 7% and ADA-low: 29%). PFS and OS were worse in ADA-high group than in ADA-low group ( P = 0.001 for PFS; P &lt; 0.001 for OS). In multivariate Cox regression analysis, the clinical significance of high ADA levels was independently associated with shorter PFS and OS after adjustment for age, sex, ECOG performance status, Child-Pugh score, AFP, macroscopic vascular invasion, extrahepatic spread, and neutrophil-to-lymphocyte ratio (PFS: HR 2.27, P = 0.006; OS: HR 3.04, P = 0.006). The atezolizumab serum concentrations were 29.8% lower in patients with high ADA levels than in ADA-negative patients. Atezolizumab concentration at C2D1 was inversely correlated with ADA levels. Moreover, patients with high ADA lacked CD8 + T cell proliferative responses to atezo/bev treatment. Furthermore, patients with high ADA had decreased secretion of effector cytokines such as IFN-γ and TNF-α from CD8 + T cells compared to those with low ADA. Conclusions: Highly elevated ADA at C2D1 is associated with unfavorable clinical outcomes in advanced HCC patients treated with atezo/bev. High ADA levels were associated with reduced atezolizumab exposure and could limit the drug’s anti-cancer efficacy.
Patient characteristics and outcomes associated with small cell lung cancer by treatment status in a U.S. Medicare population.
Authors: Robert A. Ramirez, Andy Surinach, Paul Cockrum
Journal: Journal of Clinical Oncology (2022)

e20614 Background: Globally, small cell lung cancer (SCLC) accounts for approximately 10% of lung cancers and is typically diagnosed at an advanced/extensive stage in elderly current or former smokers. The objective of this study was to describe patient characteristics (demographic and clinical) and outcomes (survival) associated with SCLC in the Medicare population by systemic anticancer treatment status (treated vs untreated). Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. Patients were included if they had a record with a diagnosis of SCLC in the database from 1/1/2007 – 12/31/2017, were ≥65 years of age at diagnosis, and had continuous enrollment for ≥180 days pre-SCLC diagnosis. Patient characteristics and overall survival (OS) were stratified by treatment status. Median OS was estimated using the Kaplan Meier method. Results: 13,516 patients met the study criteria. Overall, 57.7% were female, mean age was 74 years, and 89.5% were white. Nearly three-fourths (73.1%) were diagnosed with stage 4 disease. Just over half (55.4%, N = 6,022) initiated 1L treatment. Older patients were less likely to be treated: 36.3%, 51.1%, and 78.5% of patients 65-74 yrs, 75-84 yrs, and 85+ yrs, respectively, were untreated. Patients diagnosed at stage I-III were more likely to be treated than those diagnosed with stage IV disease (68.2% vs 51.4% treated). Patients with metastasis in the brain and/or liver were also less likely to be treated than patients without metastasis in those sites. On average untreated patients had more comorbid conditions than treated patients (average Charlson Comorbidity Index [CCI] 9.2 vs 9.5). In particular, congestive heart failure (49.3% vs 32.6%), myocardial infarction (25.7% vs 18.9%), renal disease (31.5% vs 18.9%), dementia (13.3% vs 3.5%), hemiplegia/paraplegia (8.0% vs 3.2%), and diabetes with complications (21.1% vs 16.4%) were more common among untreated patients. Median survival among untreated patients was 1.1 months (95% CI: not estimable) versus 9.2 months (95% CI:9.0-9.5 months) among treated patients. Approximately 5% of untreated patients were alive 12 months after diagnosis whereas 40% of treated patients were alive 12 months after initiating 1L treatment. Conclusions: Nearly half of SCLC patients did not initiate systemic anticancer treatment. Those who were untreated were on average older, had more comorbid conditions, were more likely to be diagnosed with stage IV disease, and had shorter survival, affirming the continued need for safe and effective therapies for SCLC.
Availability of child care resources for patients undergoing cancer treatment at NCI-designated cancer centers.
Authors: Monica Levine, Melissa Brown, Christa Nagel, Roberto Vargas, Laura Chambers
Journal: Journal of Clinical Oncology (2022)

e13508 Background: The National Cancer Institute (NCI) estimates that approximately one-quarter of adults with cancer are parents to children less than 18 years. Further, it is estimated that 2.85 million minor children in the United States have a parent undergoing cancer treatment. Previous studies have demonstrated that parents with cancer experience significant stress and disruptions to familial life following a cancer diagnosis. In a study of women with breast, gynecologic cancer and other cancers undergoing cancer therapy, 48.7% of women endorsed needing help with childcare and 64.1% needing help with household management. Despite this evidence supporting both a need for childcare among patients with cancer, data regarding the availability of on-site childcare programs and resources at NCI-designated cancer centers is limited. The objective of this cross-sectional study was to assess the availability of childcare resources for parents who are undergoing cancer treatment at NCI-Designated Cancer Centers. Methods: The availability of childcare resources for parents undergoing cancer treatment at all 51 NCI-designated comprehensive cancer centers and 13 NCI-designated cancer was assessed in January 2021 and February 2021. Childcare resources were assessed via online search and telephone calls. Specifically, centers were queried regarding availability of daycare programs for children of patients undergoing treatment and whether resources were available to assist patients in need of childcare. Descriptive statistics were performed. Results: In total, only 1/64 (1.6%) of NCI-designated cancer centers currently offer childcare resources for patients undergoing cancer treatment. This center offers childcare for children ages 2–8, free of charge with multiple outpatient locations. One additional institution previously provided patients with access to daycare, but has closed due to the COVID-19 pandemic. Further, only 1/64 (1.6%) NCI-designated cancer center offers financial assistance grants to aid patients to subsidizing childcare costs during cancer treatment. Conclusions: Institution sponsored options for childcare for patients undergoing cancer treatments are highly limited, even in the best resourced cancer care settings. The COVID-19 pandemic has limited options further, and many hospitals now restrict visitors under the age of 18. Patient grants or institutionally sponsored childcare provider networks may represent an avenue for supporting parents who are facing a cancer diagnosis. Supporting families of patients with cancer has great potential to impact quality of life, economic and psychological stress.
Distinct outcomes in Hispanic/Latinx and non-Hispanic/Latinx patients with metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab plus nivolumab (ipi/nivo).
Authors: Sana Ali, Sally Leong, Luis A Meza, Nazli Dizman, Zeynep Busra Zengin, Tane Kim, Youngju Pak, Mykola Onyshchenko, Sumanta K. Pal, Alex Chehrazi-Raffle
Journal: Journal of Clinical Oncology (2022)

4554 Background: Subgroup analyses have reported differences in clinical outcomes by ethnicity in patients (pts) receiving immune checkpoint inhibitors (Cheng et al Ann Oncol 2019; Peravali et al World J Clin Oncol 2021). We sought to compare real-world outcomes between Hispanic/Latinx and non-Hispanic/Latinx mRCC pts treated with first-line ipi/nivo within a safety-net healthcare system and at a tertiary care center in Southern California. Methods: We performed a retrospective analysis of mRCC pts who received ipi/nivo within the Los Angeles County Department of Health Services (a safety-net healthcare system) and the City of Hope Comprehensive Cancer Center (a tertiary oncology center) between Jan 1, 2015 and Dec 31, 2021. Pts were identified using institutional databases and clinical data were compiled from electronic health records. Pts with pathologic diagnosis of stage IV mRCC, age &gt; 18 years and receipt of ipi/nivo as first-line therapy were included. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. Results: Of 96 pts, 67 (70%) were male, 90 (94%) had clear-cell histology, and 89 (93%) had intermediate/poor IMDC risk. Forty-two pts (44%) were Hispanic/Latinx while the remainder were non-Hispanic/Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (52%) and 46 (48%) pts received their care at a tertiary care center and within a safety-net healthcare system, respectively. Median age, IMDC risk classification, BMI, and number of comorbidities were similar between both groups. Pooled analysis by ethnicity revealed significantly shorter PFS in Hispanic/Latinx vs non-Hispanic/Latinx pts (HR 1.60, 95% CI 1.04-2.48, p = 0.03). At 12 months, 19% of Hispanic/Latinx pts (95% CI, 9-32) and 35% of non-Hispanic/Latinx pts (95% CI, 23-48) were alive and progression-free. There was no difference in PFS between pts at the safety-net hospital system vs tertiary care center (HR 1.32, 95% CI 0.87-2.02, p = 0.19). Conclusions: Our real-world analysis of mRCC pts demonstrated poorer outcomes with ipi/nivo in Hispanic/Latinx pts. We are currently interrogating multiple social determinants of health that may contribute to these concerning disparities.
A multicenter, open-label, phase 1a/b study of HC-7366, a modulator of integrated stress response (ISR) kinase GCN2 in subjects with advanced solid tumors.
Authors: Meredith Pelster, Marcio Torre, Geoffrey Sumithran Kannan, Michele Anne Gargano, Paulette Mattson, Blaine Rathmann, Nandita Bose, Jose Luis Iglesias
Journal: Journal of Clinical Oncology (2022)

TPS3179 Background: To survive harsh tumor microenvironments, cancer cells actively utilize ISR as an adaptive stress response and survival mechanism. General control nonderepressible 2 (GCN2), a serine-threonine kinase is essential for maintaining cellular homeostasis in amino acid stress conditions. HC-7366 is a novel, highly selective, and potent GCN2 kinase modulator. Single agent HC-7366 has demonstrated potent anti-tumor activity resulting in regression and complete responses in several pre-clinical tumor models. Methods: This is a first in human, multicenter, open label, Phase 1a/b dose escalation and expansion study to establish the maximum tolerated dose, evaluate safety and tolerability, and determine the recommended Phase 2 dose of daily oral dosing of HC-7366 in patients (pts) with advanced solid tumors. Up to 36 pts with squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or transitional cell carcinoma of the bladder (TCC) will be enrolled into Phase 1a; other solid tumors are eligible if selection criteria are met (capped at 50%). A 3+3 design will be employed and dose escalation determined by occurrence of dose limiting toxicities (DLT) within Cycle 1 (21 days). A Safety Monitoring Committee will review each cohort when the planned number of pts complete the DLT period. Six dose levels (10, 20, 40, 75, 125, 150 mg) of HC-7366 will be evaluated. Phase 1b will be an expansion of up to two Phase 1a dose levels and enroll 15 pts per cohort. Secondary endpoints include ORR, DOR, TTF, PFS, and OS. Pharmacokinetic data will be profiled. Exploratory objectives include evaluation of pharmacodynamic markers in tumor biopsies and immunophenotyping in blood samples. Main inclusion criteria include: SCCHN, CRC, NSCLC, TCC or other solid tumors; &gt;1 radiologically measurable lesion per RECISTv1.1; &gt;1 biopsiable lesion at baseline; no immune checkpoint inhibitor within 4 weeks (wks) of 1 st dose; ECOG 0 or 1; &lt;10% body weight loss in 4 wks before 1 st dose &amp; serum albumin &gt;3 g/dL; and normal/adequately controlled pan-endocrine function. Main exclusion criteria include: autoimmune disease, organ transplant, retinitis or photosensitive skin disorders; history of interstitial lung disease or pneumonitis within 1yr; and overt or latent disorders of the exocrine pancreas. Formal hypothesis testing will not be performed. Descriptive statistics of parameters of interest will be presented by dose level and safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. Approximately 9 US sites will participate. Clinical trial information: NCT05121948.
Chemotherapy with significant mortality benefit in patients with bladder cancer with variant and non-urothelial histologies (NUVH).
Authors: Stuthi Perimbeti, Changchuan Jiang, Lei Deng, Arya Mariam Roy, Shilpi Gupta, Greeshma Kambam, Gurkamal S. Chatta, Saby George, Dharmesh Gopalakrishnan
Journal: Journal of Clinical Oncology (2022)

4586 Background: Non urothelial cancers and urothelial cancers with variant histologies(NUVH) have a more aggressive natural history and are at a higher risk of progression to muscle invasive disease(MIBC) when compared to their urothelial counterparts. Although surgical resection is the treatment of choice in localized disease, radiation(RT) is commonly used in patients who are not surgical candidates. The use of chemotherapy has shown modest benefit in some retrospective studies. Considering the low incidence of NUVH, there are no large-scale studies examining the benefits of chemoradiation(CRT) in MIBC with NUVH. Methods: The National Cancer Database was queried to identify MIBC patients with NUVH from the years 2004-2018.Inclusion criteria for the study are age &gt; 18 years, Non urothelial or variant histologies and receipt of RT. Patients who underwent cystectomy or had metastatic disease were excluded. The population was divided into two cohorts if they received chemoradiation. Chi-Square test and Mann Whitney U tests were used to compare frequency distributions. Cox proportional Hazard regression was employed to control for confounding factors associated with overall survival. Covariates for confounding included age, race, sex, income, insurance status, charlson-deyo comorbidity index, education. Results: Among 1773 observations in the final analysis, 63.05%(n = 1118) received CRT. Small cell, large cell and neuroendocrine cancers composed of the majority of NUVH. 38.01% (n = 641). Other histologies composed of squamous cell cancer 30.34%(n = 538), spindle cell/sarcomatoid cancers10.15%(180), adenocarcinoma 11.44%(203). Patients who received CRT were found to be significantly younger (76 vs 82 years P: &lt; 0.0001) with higher male predominance74.73%. 5 year overall mortality was significaantly lower in the CRT vs RT group ( 66.47% vs 81.55%, p &lt; 0.001). After controlling for confounding factors, CRT was associated with lower risk of mortality Hazard Ratio(HR)of 0.41(0.36-0.47) p &lt; 0.0001. Added, the survival benefit of CRT continued in the non small cell variant cohort HR: 0.43(0.37-0.51) P &lt; 0.0001. Conclusions: In this large retrospective study, CRT was associated with reduced overall mortality among patients with non-urothelial MIBC. The findings suggest the importance of systemic therapy in providing a survival advantage to non-urothelial MIBC, including the non-small cell variants. [Table: see text]
Olanzapine with or without an NK-1 receptor antagonist for preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy: A phase III randomized, double-blind, placebo-controlled trial (ALLIANCE A221602).
Authors: Rudolph M. Navari, Jennifer Le-Rademacher, Fabrice Smieliauskas, Kathryn Jean Ruddy, Thomas James Saphner, Heshan Liu, Beth Harlos, Adedayo A. Onitilo, Karthik Giridhar, Preet Paul Singh, Pavan S. Reddy, Flavio Kruter, George Raptis, Charles L. Loprinzi
Journal: Journal of Clinical Oncology (2022)

12107 Background: Chemotherapy-induced nausea and vomiting (CINV), a major adverse effect of cancer treatment, can attenuate life quality. Multiple international antiemetic guidelines have recommended a 4-drug regimen (corticosteroid, 5-HT3 receptor antagonist, NK-1 receptor antagonist, and the antipsychotic medication olanzapine) for decreasing highly emetogenic CINV. This raised a question regarding whether antiemetic therapy regimens for highly emetogenic chemotherapy could be de-intensified, decreasing cost and side effects from anti-emetogenic agents. Methods: Study A221602 was developed to compare two olanzapine-containing antiemetic regimens, one with the use of an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Patients (pts) received intravenous highly emetogenic chemotherapy as either 1) cisplatin, given on one day, at a dose of ≥ 70 mg/m2, with or without other chemotherapy agent(s) or 2) doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) on one day. Pts in both arms received 1) a 5-HT 3 receptor antagonist (palonosetron 0.25 mg IV or ondansetron 8-16 mg IV or 16-24 mg PO,) on day one, 2) dexamethasone (12 mg PO, day one followed by 8 mg PO, days 2-4), and 3) olanzapine (10 mg/day PO, days 1 to 4). On Day 1, all agents were given prior to chemotherapy, with the exception that olanzapine could be taken prior to chemotherapy or at bedtime. Additionally, pts were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV; 346 pts) or a matching placebo (344 pts). The primary objective was to compare the proportion of patients with no nausea for 5 days following receipt of their chemotherapy between the two study arms. Results: While there was no suggestion of outcome differences on day 1 between the two study arms, fewer pts (7.4%; upper limit of the 95% confidence interval was 13.5%) without NK-1 receptor antagonists were without nausea for the complete 5-day study period. Conclusions: Per the study design, created to exclude a 10% benefit for NK-1 receptor antagonists, the results did not provide sufficient evidence to reject the hypothesis that the 4-drug regimen was superior to the protocol 3-drug regimen (p=0.24). Support: UG1CA189823; Clinical trial information: NCT03578081.
ELU-FRα-1: A study to evaluate ELU001 in patients with solid tumors that overexpress folate receptor alpha (FRα).
Authors: Wen Wee Ma, Anthony W. Tolcher, James Fredric Strauss, Tanios S. Bekaii-Saab, Yujie Zhao, Cesar Augusto Perez, Erika P. Hamilton, Gregory Paul Adams, Catherine Reddick, Eliel Bayever
Journal: Journal of Clinical Oncology (2022)

TPS3158 Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ̃12 folic acid targeting moieties and ̃22 exatecan topoisomerase-1 inhibitor payloads on Cathepsin-B cleavable linkers covalently bound to the surface of each silicon core/polyethylene glycol C’Dot nanoparticle. CDCs are small in size (̃6 nm), have a greater ability to penetrate into and through tumors as compared to ADCs, and are rapidly eliminated by the kidneys. The rapid systemic elimination is expected to lead to less toxicity than is observed with targeting platforms like ADCs that have a longer half-life in circulation. ELU001’s high avidity is believed to promote internalization into FRα overexpressing cancer cells, selectively delivering it’s ̃22 molecules of payload. The first-in-human clinical trial, ELU-FRα-1, is currently recruiting patients that have advanced, recurrent or refractory FRα overexpressing tumors considered to be topoisomerase 1 inhibitor-sensitive based on the literature, and, in the opinion of the Investigator, have no satisfactory therapeutic options available. Methods: This is a Phase 1 / 2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). In Part 1, patients with cancer types with a high likelihood of having FRα overexpressing tumors based on historical data, (specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma), will be enrolled to the study. Patients will receive ELU001 on a weekly dose regimen (QW) (once a week for 3 weeks, 1 week rest) or every other week dose regimen (Q2W, with no rest between cycles). Retrospective analysis of FRα expression will be determined. Part 2 uses a Simon’s Two-Stage design to evaluate 4-6 tumor group expansion cohorts, each consisting of patients with specific tumor types (to be identified based on emerging data) that overexpress FRα (prospectively determined prior to enrollment). The primary objective for Part 1 is to identify the MTD/RP2D and for Part 2 is ORR. Dose Escalation will recruit about 25 patients per dose regimen (QW or Q2W). Dose Expansion will recruit about 15 patients per tumor group expansion cohort. Secondary objectives are anti-tumor activity (DOR, PFS, TFST, PFS2, OS), frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. The study is actively enrolling in the US – Cohorts 1-2 have been completed without DLT. Enrollment to Cohort 3 began in December 2021. Clinical trial information: NCT05001282 .